Gliomas are the most malignant and aggressive form of brain tumors, and account for the majority of brain cancer related deaths. Malignant gliomas, including glioblastoma are treated with radiation and temozolomide, with only a minor benefit in survival time. A number of advances have been made in understanding glioma biology, including the discovery of cancer stem cells, termed glioma stem cells (GSC). Some of these advances include the delineation of molecular hetereogeneity both between tumors from different patients as well as within tumors from the same patient. Such research highlights the importance of identifying and validating molecular markers in glioma. This review, intended as a practical resource for both clinical and basic investigators, summarizes some of the more well-known molecular markers (MGMT, 1p/19q, IDH, EGFR, p53, PI3K, Rb, and RAF), discusses how they are identified, and what, if any, clinical relevance they many have, in addition to discussing some of the specific biology for these markers. Additionally, we discuss identification methods for studying putative GSC’s (CD133, CD15, A2B5, Nestin, ALDH1, Proteasome activity, ABC transporters, and Label-retention). While much research has been done on these markers, there is still a significant amount that we do not yet understand, which may account for some conflicting reports in the literature. Furthermore, it is unlikely that the investigator will be able to utilize one single marker to prospectively identify and isolate GSC from all, or possibly, any gliomas.

BackgroundThere is considerable interest in defining the metabolic abnormalities of IDH mutant tumors to exploit for therapy. While most studies have attempted to discern function by using cell lines transduced with exogenous IDH mutant enzyme, in this study, we perform unbiased metabolomics to discover metabolic differences between a cohort of patient-derived IDH1 mutant and IDH wildtype gliomaspheres.MethodsUsing both our own microarray and the TCGA datasets, we performed KEGG analysis to define pathways differentially enriched in IDH1 mutant and IDH wildtype cells and tumors. Liquid chromatography coupled to mass spectrometry analysis with labeled glucose and deoxycytidine tracers was used to determine differences in overall cellular metabolism and nucleotide synthesis. Radiation-induced DNA damage and repair capacity was assessed using a comet assay. Differences between endogenous IDH1 mutant metabolism and that of IDH wildtype cells transduced with the IDH1 (R132H) mutation were also investigated.ResultsOur KEGG analysis revealed that IDH wildtype cells were enriched for pathways involved in de novo nucleotide synthesis, while IDH1 mutant cells were enriched for pathways involved in DNA repair. LC-MS analysis with fully labeled 13C-glucose revealed distinct labeling patterns between IDH1 mutant and wildtype cells. Additional LC-MS tracing experiments confirmed increased de novo nucleotide synthesis in IDH wildtype cells relative to IDH1 mutant cells. Endogenous IDH1 mutant cultures incurred less DNA damage than IDH wildtype cultures and sustained better overall growth following X-ray radiation. Overexpression of mutant IDH1 in a wildtype line did not reproduce the range of metabolic differences observed in lines expressing endogenous mutations, but resulted in depletion of glutamine and TCA cycle intermediates, an increase in DNA damage following radiation, and a rise in intracellular ROS.ConclusionsThese results demonstrate that IDH1 mutant and IDH wildtype cells are easily distinguishable metabolically by analyzing expression profiles and glucose consumption. Our results also highlight important differences in nucleotide synthesis utilization and DNA repair capacity that could be exploited for therapy. Altogether, this study demonstrates that IDH1 mutant gliomas are a distinct subclass of glioma with a less malignant, but also therapy-resistant, metabolic profile that will likely require distinct modes of therapy.Electronic supplementary materialThe online version of this article (10.1186/s40170-018-0177-4) contains supplementary material, which is available to authorized users.

The cytokinetic furrow (CF) is organized by the RhoA GTPase, which recruits actin and myosin II to the furrow and drives contractility. Here we show a role for the RhoGAP, p190, in cytokinesis and its involvement in regulating Rho GTP levels and contractility. Cells depleted of p190RhoGAP (p190) accumulate high levels of RhoGTP and markers of high Rho activity in the furrow, resulting in failure of the CF to progress to abscission. The loss of p190 can be rescued by a low dose of the myosin II inhibitor blebbistatin, suggesting that cells fail cytokinesis because they have too much myosin activity. p190RhoGAP binds the cytokinetic organizer anillin, and mutants of p190 that are unable to bind anillin or unable to inactivate Rho fail to rescue cytokinesis defects in p190-depleted cells. Together these data demonstrate that a complex of p190RhoGAP and anillin modulates RhoGTP levels in the CF to ensure robust cytokinesis.

Tumor necrosis factor-α (TNF)-induced apoptotic activation of caspase-8 requires internalization of its receptor. This study shows that constitutively activated β-catenin is required to facilitate the lysosomal delivery of internalized TNF, the inhibition of caspase-8 activation, and the suppression of apoptosis in colon cancer cells.

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